Human Genetics

, Volume 129, Issue 5, pp 573–582 | Cite as

Mutations in Fanconi anemia genes and the risk of esophageal cancer

  • Mohammad R. Akbari
  • Reza Malekzadeh
  • Pierre Lepage
  • David Roquis
  • Ali R. Sadjadi
  • Karim Aghcheli
  • Abbas Yazdanbod
  • Ramin Shakeri
  • Jafar Bashiri
  • Masoud Sotoudeh
  • Akram Pourshams
  • Parviz Ghadirian
  • Steven A. Narod
Original Investigation

Abstract

The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northeastern Iran. Previously, we reported a strong familial component of ESCC among Turkmens, who constitute approximately one-half of the population of this region. We hypothesized that the genes which cause Fanconi anemia might be candidate genes for ESCC. We sequenced the entire coding regions of 12 Fanconi anemia genes in the germline DNA of 190 Turkmen cases of ESCC. We identified three heterozygous insertion/deletion mutations: one in FANCD2 (p.Val1233del), one in FANCE (p.Val311SerfsX2), and one in FANCL (p.Thr367AsnfsX13). All three patients had a strong family history of ESCC. In addition, four patients (out of 746 tested) were homozygous for the FANCA p.Ser858Arg mutation, compared to none of 1,373 matched controls (OR = 16.7, 95% CI = 6.2–44.2, P = 0.01). The p. Lys3326X mutation in BRCA2 (also known as Fanconi anemia gene FANCD1) was present in 27 of 746 ESCC cases and in 16 of 1,373 controls (OR = 3.38, 95% CI = 1.97–6.91, P = 0.0002). In summary, both heterozygous and homozygous mutations in several Fanconi anemia-predisposing genes are associated with an increased risk of ESCC in Iran.

Supplementary material

439_2011_951_MOESM1_ESM.doc (646 kb)
Supplementary material 1 (DOC 645 kb)

References

  1. Adachi D, Oda T, Yagasaki H, Nakasato K, Taniguchi T, D’Andrea AD et al (2002) Heterogeneous activation of the Fanconi anemia pathway by patient-derived FANCA mutants. Hum Mol Genet 11:3125–3134PubMedCrossRefGoogle Scholar
  2. Akbari MR, Malekzadeh R, Nasrollahzadeh D, Amanian D, Sun P, Islami F et al (2006) Familial risks of esophageal cancer among the Turkmen population of the Caspian littoral of Iran. Int J Cancer 119:1047–1051PubMedCrossRefGoogle Scholar
  3. Akbari MR, Malekzadeh R, Nasrollahzadeh D, Amanian D, Islami F, Li S et al (2008) Germline BRCA2 mutations and the risk of esophageal squamous cell carcinoma. Oncogene 27:1290–1296PubMedCrossRefGoogle Scholar
  4. Ali AM, Kirby M, Jansen M, Lach FP, Schulte J, Singh TR et al (2009) Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group. Hum Mutat 30:E761–E770PubMedCrossRefGoogle Scholar
  5. Alpi AF, Pace PE, Babu MM, Patel KJ (2008) Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell 32:767–777PubMedCrossRefGoogle Scholar
  6. Alter BP (2003) Cancer in Fanconi anemia, 1927–2001. Cancer 97:425–440PubMedCrossRefGoogle Scholar
  7. Alter BP, Joenje H, Oostra AB, Pals G (2005) Fanconi anemia: adult head and neck cancer and hematopoietic mosaicism. Arch Otolaryngol Head Neck Surg 131:635–639PubMedCrossRefGoogle Scholar
  8. Callén E, Tischkowitz MD, Creus A, Marcos R, Bueren JA, Casado JA, Mathew CG, Surrallés J (2004) Quantitative PCR analysis reveals a high incidence of large intragenic deletions in the FANCA gene in Spanish Fanconi anemia patients. Cytogenet Genome Res 104:341–345PubMedCrossRefGoogle Scholar
  9. Couch FJ, Johnson MR, Rabe K, Boardman L, McWilliams R, de Andrade M, Petersen G (2005) Germline Fanconi anemia complementation group C mutations and pancreatic cancer. Cancer Res 65:383–386PubMedGoogle Scholar
  10. Djuzenova CS, Rothfuss A, Oppitz U, Spelt G, Schindler D, Hoehn H, Flentje M (2001) Response to X-irradiation of Fanconi anemia homozygous and heterozygous cells assessed by the single-cell gel electrophoresis (comet) assay. Lab Invest 81:185–192PubMedGoogle Scholar
  11. Futaki M, Yamashita T, Yagasaki H, Toda T, Yabe M, Kato S, Asano S, Nakahata T (2000) The IVS4 + 4 A to T mutation of the Fanconi anemia gene FANCC is not associated with a severe phenotype in Japanese patients. Blood 95:1493–1498PubMedGoogle Scholar
  12. Gordon SM, Alon N, Buchwald M (2005) FANCC, FANCE, and FANCD2 form a ternary complex essential to the integrity of the Fanconi anemia DNA damage response pathway. J Biol Chem 280:36118–36125PubMedCrossRefGoogle Scholar
  13. Houghtaling S, Timmers C, Noll M, Finegold MJ, Jones SN, Meyn MS, Grompe M (2003) Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice. Genes Dev 17:2021–2035PubMedCrossRefGoogle Scholar
  14. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C et al (2002) Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297:606–609PubMedCrossRefGoogle Scholar
  15. Islami F, Kamangar F, Aghcheli K, Fahimi S, Semnani S, Taghavi N et al (2004) Epidemiologic features of upper gastrointestinal tract cancers in Northeastern Iran. Br J Cancer 90:1402–1406PubMedCrossRefGoogle Scholar
  16. Joenje H, Patel KJ (2001) The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet 2:446–457PubMedCrossRefGoogle Scholar
  17. Kalb R, Neveling K, Hoehn H, Schneider H, Linka Y, Batish SD et al (2007) Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype. Am J Hum Genet 80:895–910PubMedCrossRefGoogle Scholar
  18. Levitus M, Joenje H, de Winter JP (2006) The Fanconi anemia pathway of genomic maintenance. Cell Oncol 28:3–29PubMedGoogle Scholar
  19. Li G, Hu N, Goldstein AM, Tang ZZ, Roth MJ, Wang QH et al (2001) Allelic loss on chromosome bands 13q11–q13 in esophageal squamous cell carcinoma. Genes Chromosomes Cancer 31:390–397PubMedCrossRefGoogle Scholar
  20. Lowenfels AB, Maisonneuve P (2005) Risk factors for pancreatic cancer. J Cell Biochem 95:649–656PubMedCrossRefGoogle Scholar
  21. Martin ST, Matsubayashi H, Rogers CD, Philips J, Couch FJ, Brune K et al (2005) Increased prevalence of the BRCA2 polymorphic stop codon K3326X among individuals with familial pancreatic cancer. Oncogene 24:3652–3656PubMedCrossRefGoogle Scholar
  22. Mazoyer S, Dunning AM, Serova O, Dearden J, Puget N, Healey CS et al (1996) A polymorphic stop codon in BRCA2. Nat Genet 14:253–254PubMedCrossRefGoogle Scholar
  23. McAllister KA, Bennett LM, Houle CD, Ward T, Malphurs J, Collins NK et al (2002) Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene. Cancer Res 62:990–994PubMedGoogle Scholar
  24. McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S et al (2003) Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 66:8109–8115CrossRefGoogle Scholar
  25. Medhurst AL, Laghmani el H, Steltenpool J, Ferrer M, Fontaine C, de Groot J et al (2006) Evidence for subcomplexes in the Fanconi anemia pathway. Blood 108:2072–2080PubMedCrossRefGoogle Scholar
  26. Mirchandani KD, D’Andrea AD (2006) The Fanconi anemia/BRCA pathway: a coordinator of cross-link repair. Exp Cell Res 312:2647–2653PubMedCrossRefGoogle Scholar
  27. Murphy TJ, Ravi N, Reynolds JV (2008) Treatment options for esophageal cancer. Expert Opin Pharmacother 9:3197–3210PubMedCrossRefGoogle Scholar
  28. Narod SA (2002) Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2:1372–1375CrossRefGoogle Scholar
  29. Nasrollahzadeh D, Kamangar F, Aghcheli K, Sotoudeh M, Islami F, Abnet CC et al (2008) Opium, tobacco, and alcohol use in relation to oesophageal squamous cell carcinoma in a high-risk area of Iran. Br J Cancer 98:1857–1863PubMedCrossRefGoogle Scholar
  30. Neveling K, Endt D, Hoehn H, Schindler D (2009) Genotype-phenotype correlations in Fanconi anemia. Mutat Res 668:73–91PubMedCrossRefGoogle Scholar
  31. Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814PubMedCrossRefGoogle Scholar
  32. Nookala RK, Hussain S, Pellegrini L (2007) Insights into Fanconi Anaemia from the structure of human FANCE. Nucleic Acids Res 35:1638–1648PubMedCrossRefGoogle Scholar
  33. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRefGoogle Scholar
  34. Pearson T, Jansen S, Havenga C, Stones DK, Joubert G (2001) Fanconi anemia A statistical evaluation of cytogenetic results obtained from South African families. Cancer Genet Cytogenet 126:52–55PubMedCrossRefGoogle Scholar
  35. Pellegrini L, Yu DS, Lo T, Anand S, Lee M, Blundell TL, Venkitaraman AR (2002) Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature 420:287–293PubMedCrossRefGoogle Scholar
  36. Pourshams A, Khademi H, Malekshah AF, Islami F, Nouraei M, Sadjadi AR et al (2010) Cohort Profile: the Golestan Cohort Study—a prospective study of oesophageal cancer in northern Iran. Int J Epidemiol 39:52–59PubMedCrossRefGoogle Scholar
  37. Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R et al (2007) Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 39:162–164PubMedCrossRefGoogle Scholar
  38. Rosenberg PS, Greene MH, Alter BP (2003) Cancer incidence in persons with Fanconi anemia. Blood 101(3):822–826PubMedCrossRefGoogle Scholar
  39. Rosenberg PS, Alter BP, Ebell W (2008) Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry. Haematologica 93:511–517PubMedCrossRefGoogle Scholar
  40. Rozen S, Skaletsky HJ (2000) Primer3 on the WWW for general users and for biologist programmers. In: Krawetz S, Misener S (eds) Bioinformatics methods and protocols: methods in molecular biology. NJ Humana Press, Totowa, pp 365–386Google Scholar
  41. Rudd MF, Webb EL, Matakidou A, Sellick GS, Williams RD, Bridle H et al (2006) Variants in the GH-IGF axis confer susceptibility to lung cancer. Genome Res 16:693–701PubMedCrossRefGoogle Scholar
  42. Sadjadi A, Malekzadeh R, Derakhshan MH, Sepehr A, Nouraie M, Sotoudeh M et al (2003) Cancer occurrence in Ardabil: results of a population-based cancer registry from Iran. Int J Cancer 107:113–118PubMedCrossRefGoogle Scholar
  43. Saidi F, Sepehr A, Fahimi S, Farahvash MJ, Salehian P, Esmailzadeh A et al (2000) Oesophageal cancer among the Turkomans of northeast Iran. Br J Cancer 83:1249–1254PubMedCrossRefGoogle Scholar
  44. Savino M, Borriello A, D’Apolito M, Criscuolo M, Del Vecchio M, Bianco AM et al (2003) Spectrum of FANCA mutations in Italian Fanconi anemia patients: identification of six novel alleles and phenotypic characterization of the S858R variant. Hum Mutat 22:338–339PubMedCrossRefGoogle Scholar
  45. Semnani S, Sadjadi A, Fahimi S, Nouraie M, Naeimi M, Kabir J et al (2006) Declining incidence of esophageal cancer in the Turkmen Plain, eastern part of the Caspian littoral of Iran: a retrospective cancer surveillance. Cancer Detect Prev 30:14–19PubMedCrossRefGoogle Scholar
  46. Simard J, Dumont M, Labuda D, Sinnett D, Meloche C, El-Alfy M et al (2003) Prostate cancer susceptibility genes: lessons learned and challenges posed. Endocr Relat Cancer 10:225–259PubMedCrossRefGoogle Scholar
  47. Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER, Hurov KE, Luo J et al (2007) Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 129:289–301PubMedCrossRefGoogle Scholar
  48. Sunyaev S, Ramensky V, Koch I, Lathe W, Kondrashov AS, Bork P (2001) Prediction of deleterious human alleles. Hum Mol Genet 10:591–597PubMedCrossRefGoogle Scholar
  49. Tamary H, Bar-Yam R, Shalmon L, Rachavi G, Krostichevsky M, Elhasid R et al (2000) Fanconi anaemia group A (FANCA) mutations in Israeli non-Ashkenazi Jewish patients. Br J Haematol 111:338–343PubMedCrossRefGoogle Scholar
  50. Taniguchi T, D’Andrea AD (2006) Molecular pathogenesis of Fanconi anemia: recent progress. Blood 107:4223–4233PubMedCrossRefGoogle Scholar
  51. Tischkowitz MD, Morgan NV, Grimwade D, Eddy C, Ball S, Vorechovsky I et al (2004) Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia. Leukemia 18:420–425PubMedCrossRefGoogle Scholar
  52. Tischkowitz M, Easton DF, Ball J, Hodgson SV, Mathew CG (2008) Cancer incidence in relatives of British Fanconi Anaemia patients. BMC Cancer 8:257PubMedCrossRefGoogle Scholar
  53. Titus TA, Selvig DR, Qin B, Wilson C, Starks AM, Roe BA, Postlethwait JH (2006) The Fanconi anemia gene network is conserved from zebrafish to human. Gene 371:211–223PubMedCrossRefGoogle Scholar
  54. Wijker M, Morgan NV, Herterich S, van Berkel CG, Tipping AJ, Gross HJ et al (1999) Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene. Eur J Hum Genet 7:52–59PubMedCrossRefGoogle Scholar
  55. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J et al (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792PubMedCrossRefGoogle Scholar
  56. Yagasaki H, Hamanoue S, Oda T, Nakahata T, Asano S, Yamashita T (2004) Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population. Hum Mutat 24:481–490PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Mohammad R. Akbari
    • 1
    • 2
    • 3
  • Reza Malekzadeh
    • 1
  • Pierre Lepage
    • 4
  • David Roquis
    • 4
  • Ali R. Sadjadi
    • 1
  • Karim Aghcheli
    • 1
  • Abbas Yazdanbod
    • 5
  • Ramin Shakeri
    • 1
  • Jafar Bashiri
    • 1
  • Masoud Sotoudeh
    • 1
  • Akram Pourshams
    • 1
  • Parviz Ghadirian
    • 6
  • Steven A. Narod
    • 2
  1. 1.Digestive Disease Research Center, Shariati HospitalTehran University of Medical SciencesTehranIran
  2. 2.Women’s College Research InstituteUniversity of TorontoTorontoCanada
  3. 3.Institute of Medical Science, Faculty of MedicineUniversity of TorontoTorontoCanada
  4. 4.Genome Quebec Innovation CentreMcGill UniversityMontrealCanada
  5. 5.Department of Internal MedicineArdabil University of Medical ScienceArdabilIran
  6. 6.Epidemiology Research Unit Research Centre, CHUM-Hôtel-DieuUniversity of MontrealMontrealCanada

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